Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma frequently found in immunocompromised patients. Despite antiretroviral therapy, KS remains common among HIV-infected patients. Existing anti-herpesviral drugs and anticancer therapeutic methods are ineffective for treating KSHV-induced cancers. KSHV infection is for life- long, however, there is no vaccine for KSHV and no method for clearing KSHV persistent infection. Despite intensive studies, the critical host factors required for KSHV-induced cancers and KSHV persistent infection remain unclear mainly because of the lack of appropriate experimental system. Our team has developed two novel systems for (a) KSHV-induced cell growth transformation and tumorigenesis, and (b) KSHV persistent infection in NOD/SCID IL2R?-/- (NSG) humanized mice. Using these novel systems, our studies have revealed KSHV extensive reprograming of cellular chromatins and gene expression networks, and identified several cellular pathways that are required for the growth and survival of KSHV latent/transformed cells. In particular, inhibitors of class III histone deacetylases (sirtuins) inuce massive cell death of KSHV-transformed cells but have minimal cytotoxicity to uninfected cells. The objective of this project is to identify and validate host factors and inhibitors targeting individual or combined cellular pathways that are essential for KSHV oncogenesis and persistent infection. Our hypothesis is that KSHV hijacks specific cellular pathways to promote cell growth and survival, and therefore therapeutic targeting of these pathways is effective for KSHV oncogenesis and persistent infection. We plan to accomplish the objective by delineating host factors and validating inhibitors targeting individual or combined cellular functions that are essential for KSHV oncogenesis and persistent infection (Aim 1); determining the mechanism by which sirtuins mediate the survival of KSHV- transformed cells (Aim 2); and examining the effects of targeting sirtuins on KSHV oncogenesis and persistent infection in animal models (Aim 3). In addition to the novel animal models, we will apply several innovative technologies such as single-molecule fluorescent in situ hybridization (SMFISH) to accomplish these aims. The proposed project is highly significant because it will identify therapeutic cellular targets an their inhibitors for viral persistent infections and pathogenesis. The results will provide insight into the mechanisms of KSHV- induced oncogenic addiction and persistent infection. The outcomes could also be applied to other virus- induced cancers and persistent viral infections.